DEFINING EVO DEVO
NOVA: There has been all this buzz about evo devo. What's the key idea, and why is it so exciting?
Cliff Tabin: Evolutionary developmental biology, or "evo devo," is a broad term that encompasses a lot of things. And different people use the term slightly differently, and also what makes it interesting for them differs from scientist to scientist.
For me, I start by taking a look at the developmental side. The revolution in developmental biology, and the revolution in biological sciences as a whole, has gotten us to the point where we actually can start to understand how genes make an embryo form the way it does, why a limb forms in the first place, and then why the arm is different from the leg, why the heart that starts as a tube in the middle folds up to be on the left and not the right. We're starting to understand those sorts of really fundamental questions, and that's amazing in itself.
We are also getting to the point where we can understand not only how you make a limb, but how the process can be altered in what are actually subtle ways such that the limb takes the form of a bat wing versus a human hand versus a flipper. And that to me is enormously exciting.
So, to me, the fundamental aspect of evo devo is understanding how development is tweaked over evolutionary time.
One of the key discoveries in evo devo is how similar our genes are to those of all other animals, right?
Yes. One of the most amazing surprises over the time I've been in science has been the finding that the genes that are involved in making animals as different as a fruit fly and a human being are fundamentally the same genes. When we thought about such things, say, 20 years ago, one had to assume that the genes to make a fruit fly would include instructions for wings, genes that we didn't need. And, conversely, that we'd have genes dedicated to making a human limb or human heart that a fly would never have. The stunning finding was that, to a first approximation, the same genes are present in both and are being used in both.
It is the most beautiful process seeing organization emerge.
Now, with hindsight, we realize, of course, that flies and humans are both animals. We had a common ancestor. Maybe it was a nondescript little wormlike thing, but that little wormlike thing already had the set of genes that made its head different from its tail and its gut different from its heart. For that worm to evolve into a fly, or to evolve ultimately into a human, those genes were used in different ways, in different combinations, with different timing.
Fundamentally, the genetic toolkit, as we call it, was already there in the common ancestor. And that ancestral set of genes was powerful and versatile enough to provide the material for generating the diverse forms of animal life we now see on Earth. That was something that nobody expected, and it's made the study of various organisms very profound. It means what you learn from studying the development of a fly really has direct implications for understanding the way we are made ourselves, because as different as a fly is from a human and as long ago as we diverged, we're using basically the same genes to do the same thing—to make organization emerge in an embryo. [See Genetic Tool Kit.]
And you and other biologists never saw it coming.
I would have bet anything that that wouldn't be the case. I would have thought that the genes involved in making a fly would be different from those that make a human. I also would have thought it would take a lot more fundamental genes within that toolkit to make a human. I would have thought the genes you use to trigger the formation of a heart would be totally different from the ones you would use to make a bone, which would be totally different from the ones you use to make the front side of an embryo different from the back side of an embryo, and so on.
It turns out the same gene or genes are used over and over again, just in different ways and combinations with other genes in a cell. And we're using what I would consider to be, based on my prior intuition, a ridiculously small number of genes.
ALL ABOUT THE EMBRYO
The fact that we all share a common set of genes is readily apparent at the embryonic stage, isn't it? Very early in their development, all animals look largely similar.
Yes. One of the things that's been discussed since the 1800s is that if you look at embryos of different vertebrates—whether it's a fish, salamander, frog, chicken, mouse, or human—at early stages they look very similar. In fact, they go through steps where they're close to indistinguishable. A serious professional looking at them closely under a microscope can tell differences almost from the start, of course. But the similarity at the early stages is really remarkable. [See Guess the Embryo.]
One of the reasons I think that's the case is that the early aspects of putting legs in the right place, making the head different from the body, those very early and very fundamental things have to take place at a certain scale dictated by the range at which key molecules are able to act. So when we're all at about the same size, whether you're a porpoise or a human or a monkey, the same sort of processes are taking place. Then after that you elaborate the differences. So at the early stages it's not just a layperson who thinks they look similar; in fundamental ways they really are similar.
One of the great moments in the history of evolution is when a fin first evolved into a limb.
It's astonishing to watch a time-lapse of a developing embryo, of any animal. You must have a fun job.
One of the great things about my field is just the opportunity to watch embryos unfold. It is the most beautiful process seeing organization emerge, whether you're seeing it in time-lapse photography or you're looking at it under a microscope over time. It is stunningly beautiful to watch it happen, and the whole process itself is so fundamentally beautiful that the aesthetics combined with the logic is just overwhelming.
TWEAKING THE BEAK
Why did you decide to study beak formation in Darwin's finches?
Well, as the technology has advanced, and as our knowledge about development has grown, it got to the point where it became realistic to think about trying to understand how developmental instructions were tweaked to give variety in nature. We didn't want to look at vastly different animals, because there would be a lot of differences between them, and it would be too hard to sort out what is really going on. We wanted to look at animals that are very closely related and that ideally have just one structure that differs in a very important way between species.
Darwin's finches in the Galapagos are a great example of that. They are birds that are essentially the same organism, but they have beaks that are very different shapes. That diversity in beak shape has allowed them to have very different lifestyles. A beak is a fundamentally important structure—it has a great ecological importance—and these different finch species were just a single bird species a million years ago. So that's one reason why Darwin's finches were very appealing to us.
And what did you find?
Before we did our research it was possible that completely different genes were involved in making beaks of different shapes. We didn't think that was likely, based on what we knew about how genes control development, but it was possible. What we found reinforced the general emerging picture: that the same genes are involved in making a sharp, pointy beak or a big, broad, nut-cracking beak. What makes all the difference is how much you turn a gene on, when you turn it on, when you turn if off—the subtle differences in regulation. Specific genes are essential to make any beak, but it's the tweaking—the amount of the gene, the timing of the gene, the duration of the gene—that's actually doing the trick.
AN ARM AND A LEG
Does the same sort of tweaking go into the formation of limbs?
Yes, and at this point, in a very fundamental way, we understand a large part of the molecular regulation, the genes that tell the limb how to form. We understand how an early mass of cells gets information that tells one group to become one structure and one group to become another. We understand how tissue starts to form a bone as opposed to a tendon, for instance. In a very fundamental way, we now know the genes that are responsible for making your limb the way it is.
That make an arm as opposed to a leg, for example?
Right. As I said earlier, the fundamental structure of a limb that we see in our arm, say, is recapitulated with some variation in different animals to serve as a wing or a flipper. But you'll also see variation in the structure a limb takes within your own body. An arm and a leg are fundamentally similar structures—for example, as you move from the shoulder or the hip toward the fingers or toes, you have a single bone in the upper limb, followed by two bones in the lower limb, then many bones forming the five digits. The fore and the hind limb are built on the same basic plan.
I don't think you need to watch nature shows to be bowled over by the diversity of life on Earth.
We now know that there are specific genes that are turned on in the hind limb, in the leg, that are not turned on in the forelimb, the arm. When they're turned on, that early limb bud gets more of a leg character. There are other genes that are present only in the forelimb or the arm at the early stages in the limb bud. So, fundamentally, the difference between an arm and a leg can be traced back to differences in genes within the early limb bud. Those fore- or hind-limb-specific genes influence the general set of limb instructions being laid down by other genes, such that the outcome is an arm or a leg.
We take our limbs for granted, but the evolution of the limb from a fish's fin way back when was a huge leap forward, wasn't it?
One of the great moments in the history of evolution is when a fin first evolved into a limb. This was something that occurred in a fish that was living in shallow water and was learning to manipulate itself in the shallows. What it did was develop a structure that could rotate and that had segments that could independently move relative to one another that terminated in digits, which was something that gave this fish the great ability to get around in the muck. It turned out to be a basic feature that had enormous potential, enormous flexibility.
Because what we see is that the basic plan of that limb—one bone in the upper limb, two bones in the lower limb, wrists that twist, a series of five or fewer digits—has been elaborated to give you everything from the wing of the bat for soaring, to a flipper of a porpoise for swimming and navigating the oceans, to a hand for grasping or playing the piano, to a mole's limb for digging. The enormous differences in limb use have enabled subsequent animals—amphibians, reptiles, birds, mammals—to develop into an extraordinary array of lifestyles.
AN EVOLUTION REVOLUTION
The field of evo devo is really exploding, isn't it?
It's just amazing. The fast pace, I think more than anything else, is what I wouldn't have expected. I think I would have predicted that we'd eventually get to where we are in terms of understanding; I just never thought it would happen as quickly as it has. There have been technological revolutions—the sequencing revolution that allowed us to sequence entire genomes, the technology to handle huge amounts of information at the same time and sort things out. It's unbelievable what you can do and how much easier and quicker it is now than when I started. I never would have thought it would happen that fast.
How do you manage to keep up?
It's very difficult to keep up when knowledge moves so quickly. I think what you do is you keep up on the things that most interest you. When I started in biology, I read everything in the entire field of molecular biology because there was, compared to today, relatively little being done. You could read two or three journals, and you basically were able to keep up on cell biology and physiology and immunology and developmental biology and cancer biology. But now you can't even keep up on developmental biology or evolutionary biology. You pick your fields, you pick your topics, you pick your questions, and basically you keep up on what really excites you the most.
And the diversity of life as revealed through evo devo is what really excites you.
I don't think you need to watch nature shows to be bowled over by the diversity of life on Earth. You can simply take a walk at home. You see birds, squirrels, dogs. You come home and hug your child. These are things you take for granted. But if you take a step back and look at just how amazing the bird is in flight, the squirrel so perfectly adapted running up and down the tree, and so on, it is just such an amazing world. And what's incredible about this time in history from a scientific perspective is we're going to be able to understand that diversity, and that just adds to the excitement. It doesn't demystify it. It makes it all the more magical.